Role of Nlrp6 and Nlrp12 in the maintenance of intestinal homeostasis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102624/1/eji2871.pd

The mutual interplay of gut microbiota, diet and human disease

The intestinal milieu harbours the gut microbiota, consisting of a complex community of bacteria, archaea, fungi, viruses, and protozoans that bring to the host organism an endowment of cells and genes more numerous than its own. In the last ten years, mounting evidence has highlighted the prominent influence of the gut mutualistic bacterial communities on human health. Microbial colonization occurs alongside with immune system development and plays a role in intestinal physiology. The community of the gut microbiota does not undergo significant fluctuations throughout adult life. However, bacterial infections, antibiotic treatment, lifestyle, surgery, and diet might profoundly affect it. Gut microbiota dysbiosis, defined as marked alterations in the amount and function of the intestinal microorganisms, is correlated with the aetiology of chronic non-communicable diseases, ranging from cardiovascular, neurologic, respiratory, and metabolic illnesses to cancer. In this review, we focus on the interplay among gut microbiota, diet, and host to provide a perspective on the role of microbiota and their unique metabolites in the pathogenesis and/or progression of various human disorders. We discuss interventions based on microbiome studies, i.e. faecal microbiota transplantation, probiotics, and prebiotics, to introduce the concept that correcting gut dysbiosis can ameliorate disease symptoms, thus offering a new approach toward disease treatment

Inflammatory bowel disease, colorectal cancer and type 2 diabetes mellitus: the links

Abstract The co-occurrence of the three disease entities, inflammatory bowel disease (IBD), colorectal cancer (CRC), type 2diabetes mellitus (T2DM) along with inflammation and dismicrobism has been frequently reported. Some authors have even suggested that dysbiosis could be the link through a molecular crosstalk of multiple inflammatory loops including TGFβ, NFKB, TNFα and ROS among others. This review focuses on the inflammatory process along with the role of microbiota in the pathophysiology of the three diseases. The etiology of IBD is multifactorial, and like CRC and T2DM, it is associated with a widespread and sustained GI inflammation and dismicrobism, whereby an array of proinflammatory mediators and other related biomolecules are up-regulated, both locally and systematically. Such a persistent or an inadequately resolved chronic inflammation may be a causative agent, in the presence other factors, leading to several pathologies such as IBD, CRC and T2DM. TGFβ plays a crucial role in pancreatic β cell malfunctioning as glucotoxicity stimulates its signaling cascade through smad 3, IL-6 and epithelial to mesenchymal transition. Such a cascade could lead to macrophages and other cells recruitment, inflammation, then IBD and CRC. NFkB is also another key regulator in the crosstalk among the pathways leading to the three disease entities. It plays a major role in linking inflammation to cancer development through its ability to up regulate several inflammatory and tumor promoting cytokines like: IL-6, IL-1 α and TNF α, as well as genes like BCL2 and BCLXL. It activates JAK/STAT signaling network via STAT3 transcription factors and promotes epithelial to mesenchymal transition. It also increases the risk for T2DM in obese people. In brief, NFKB is a matchmaker between inflammation, IBD, cancer and diabetes. In addition, TNFα plays a pivotal role in systemic inflammation. It is increased in the mucosa of IBD patients and has a central role in its pathogenesis. It also activates other signaling pathways like NFKB and MAPK leading to CRC. It is also overexpressed in the adipose tissues of obese patients thus linking it to T2DM, chronic inflammation and consequently CRC.On the other hand, increasing evidence suggests that dysbiosis plays a role in initiating, maintaining and determining the severity of IBD. Actually, among its functions, it modulates genotoxic metabolites which are able to induce CRC, a fact proven to be sustained by stool transfer from patients with CRC. Probiotics, however, may actively prevent CRC as well as IBD and results in a significant decrease in fasting glycemia in T2DM patients. In conclusion, IBD, CRC and T2DM are commonly occurring interrelated clinical problems

The Fire Within: Microbes Inflame Tumors

The immune system and the microbiota mutually interact to maintain homeostasis in the intestine. However, components of the microbiota can alter this balance and promote chronic inflammation, promoting intestinal tumor development. We review recent advances in understanding the complex interactions between the microbiota and the innate and adaptive immune systems and discuss their potential to lead us in new directions for understanding cancer biology and treatment

The association between environmental exposures during childhood and the subsequent development of Crohn's Disease: A score analysis approach

Background Environmental factors during childhood are thought to play a role in the aetiology of Crohn's Disease (CD). In South Africa, recently published work based on an investigation of 14 childhood environmental exposures during 3 age intervals (0-5, 6-10 and 11-18 years) has provided insight into the role of timing of exposure in the future development of CD. The 'overlapping' contribution of the investigated variables however, remains unclear. The aim of this study was to perform a post hoc analysis using this data and investigate the extent to which each variable contributes to the subsequent development of CD relative to each aforementioned age interval, based on a score analysis approach. Methods Three methods were used for the score analysis. Two methods employed the subgrouping of one or more (similar) variables (methods A and B), with each subgroup assigned a score value weighting equal to one. For comparison, the third approach (method 0) involved no grouping of the 14 variables. Thus, each variable held a score value of one. Results Results of the score analysis (Method 0) for the environmental exposures during 3 age intervals (0-5, 6-10 and 11-18 years) revealed no significant difference between the case and control groups. By contrast, results from Method A and Method B revealed a significant difference during all 3 age intervals between the case and control groups, with cases having significantly lower exposure scores (approximately 30% and 40% lower, respectively). Conclusion Results from the score analysis provide insight into the 'compound' effects from multiple environmental exposures in the aetiology of CD.IS

Systematic meta-analyses, field synopsis and global assessment of the evidence of genetic association studies in colorectal cancer

Objective: To provide an understanding of the role of common genetic variations in colorectal cancer (CRC) risk, we report an updated field synopsis and comprehensive assessment of evidence to catalogue all genetic markers for CRC (CRCgene2). Design: We included 869 publications after parallel literature review and extracted data for 1063 polymorphisms in 303 different genes. Meta-Analyses were performed for 308 single nucleotide polymorphisms (SNPs) in 158 different genes with at least three independent studies available for analysis. Scottish, Canadian and Spanish data from genome-wide association studies (GWASs) were incorporated for the meta-Analyses of 132 SNPs. To assess and classify the credibility of the associations, we applied the Venice criteria and Bayesian False-Discovery Probability (BFDP). Genetic associations classified as â € positive' and â € less-credible positive' were further validated in three large GWAS consortia conducted in populations of European origin. Results: We initially identified 18 independent variants at 16 loci that were classified as â € positive' polymorphisms for their highly credible associations with CRC risk and 59 variants at 49 loci that were classified as â € less-credible positive' SNPs; 72.2% of the â € positive' SNPs were successfully replicated in three large GWASs and the ones that were not replicated were downgraded to â € less-credible' positive (reducing the â € positive' variants to 14 at 11 loci). For the remaining 231 variants, which were previously reported, our meta-Analyses found no evidence to support their associations with CRC risk. Conclusion: The CRCgene2 database provides an updated list of genetic variants related to CRC risk by using harmonised methods to assess their credibility.</p

NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth

Inflammatory bowel diseases involve the dynamic interplay of host genetics, microbiome and inflammatory response. Here, we report that NLRP12, a negative regulator of innate immunity, is reduced in human ulcerative colitis by comparing monozygotic twins and other patient cohorts. In parallel, Nlrp12-deficiency in mice caused increased colonic basal inflammation, leading to a less-diverse microbiome, loss of protective gut commensal strains (Lachnospiraceae) and increased colitogenic strains (Erysipelotrichaceae). Dysbiosis and colitis susceptibility associated with Nlrp12-deficency were reversed equally by treatment with antibodies targeting inflammatory cytokines or by administration of beneficial commensal Lachnospiraceae isolates. Fecal transplants from specific pathogen free reared mice into germ-free Nlrp12-deficient mice showed that NLRP12 and the microbiome each contribute to immune signaling that culminates in colon inflammation. These findings reveal a feed-forward loop where NLRP12 promotes specific commensals that can reverse gut inflammation, while cytokine blockade during NLRP12-deficiency can reverse dysbiosis

Gut microbiota, NLR proteins, and intestinal homeostasis

The gastrointestinal tract harbors a highly complex microbial community, which is referred to as gut microbiota. With increasing evidence suggesting that the imbalance of gut microbiota plays a significant role in the pathogenesis of multiple diseases, interactions between the host immune system and the gut microbiota are now attracting emerging interest. Nucleotide-binding and leucine-rich repeat-containing receptors (NLRs) encompass a large number of innate immune sensors and receptors, which mediate the activation of Caspase-1 and the subsequent release of mature interleukin-1β and interleukin-18. Several family members have been found to restrain rather than activate inflammatory cytokines and immune signaling. NLR family members are central regulators of pathogen recognition, host immunity, and inflammation with utmost importance in human diseases. In this review, we focus on the potential roles played by NLRs in controlling and shaping the microbiota community and discuss how the functional axes interconnecting gut microbiota with NLRs impact the modulation of colitis, inflammatory bowel diseases, and colorectal cancer.The authors acknowledge many investigators in the field whose primary data could not be cited in this review because of space limitations. This work was supported by grants from the National Institute of Allergy and Infectious Diseases (grant R01-AI029564), National Institutes of Health (grant R35CA232109), National Institute of Diabetes and Digestive and Kidney Diseases (grant P01-DK094779), and RadCCORE (grant AI067798 to J.P.Y. Ting) and ITCMS T32 (grant 5T32CA009156 to S.A. Gibson). Author contributions: H. Guo wrote the initial draft, prepared and created the figures and tables, and revised the paper. S.A. Gibson wrote the initial draft and prepared and created the figures and Table 2. J.P.Y. Ting provided oversight and leadership responsibility for this paper and edited the manuscript. Disclosures: J.P.Y. Ting reported a patent to University of North Carolina, currently pending, and is the cofounder of GoldCrest Bio, a company that is looking at the role of the microbiota in radiation sickness. H. Guo holds equity shares in GoldCrest Bio. No other disclosures were reported